The present disclosure is generally directed to novel compounds having utility as an anesthetic and/or in the treatment of disorders relating to GABA function and activity. More specifically, the present disclosure is directed to neuroactive enantiomeric 15-, 16- and 17-substituted steroids, and more specifically ent-steroids, with additional optional substituents at carbons 3, 4, 6, 7, 10 and 13, and pharmaceutically acceptable salts thereof for use as, for example, an anesthetic, as well as pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them. The present disclosure is generally directed to, for use as, for example, modulators for GABA type-A receptors. The present disclosure is further directed to pharmaceutical compositions comprising such compounds.
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system. GABA activates two types of receptors, the inotropic GABAA and the metabotropic GABAB receptor. Activation of the GABAB receptor by GABA causes hyperpolarization and a resultant inhibition of neurotransmitter release. The GABAA receptor subtype regulates neuronal excitability and rapid mood changes, such as anxiety, panic, and stress response. GABAA receptors are chloride ion channels; as a result, activation of the receptor induces increased inward chloride ion flux, resulting in membrane hyperpolarization and neuronal inhibition. Drugs that stimulate GABAA receptors, such as benzodiazepines and barbiturates, have anticonvulsive effects (by reducing neuronal excitability and raising the seizure threshold), as well as anxiolytic and anesthetic effects.
The effect of certain steroids on GABAA receptors has been well-established. As a result, researchers continue to pursue the discovery and synthesis of neuroactive steroids that may act as anesthetics and/or that may serve to provide treatment for disorders related to GABA function. In addition to anesthetic properties, neuroactive steroids may be used to treat disorders related to GABA function. For example, neuroactive steroids, such as progesterone, may be used as sedative-hypnotics, exhibiting benzodiazepine-like actions, inducing reduced sleep latency and increased non-REM sleep with only small changes in slow wave and REM sleep. Further, drugs that enhance GABA responses are often used to treat anxiety in humans. Thus, it might be expected that GABA-potentiating steroids would exhibit anxiolytic effects. Neuroactive steroids may also be used to treat depression, given that accumulating evidence suggests that patients with major depression have decreased levels of GABAergic neurosteroids and that certain treatments for depression alter levels of these steroids. Although GABA is not typically thought to play a critical role in the biology of depression, there is evidence that low GABAergic activity may predispose one to mood disorders. Finally, inhibition of NMDA receptors and enhancement of GABAA receptors appear to play important roles in mediating the acute effects of ethanol in the nervous system, while related studies suggest that GABAergic neurosteroids may be involved in some of the pharmacological effects of ethanol and that neuroactive steroids may be useful in treating ethanol withdrawal.
For example, the steroids nat-allopregnanolone (nat-1) and pregnanolone (nat-2) are known to function as allosteric modulators of GABAA receptor that enhance the actions of the neurotransmitter GABA.

The allosteric modulation of this receptor by the mirror images (enantiomers) of these compounds, ent-allopregnanolone (ent-1) and ent-pregnanolone (ent-2) are known to be weaker.

Similarly, the steroids androsterone (nat-3) and etiocholanolone (nat-4) are also allosteric modulators of GABAA receptors.

Surprisingly, the enantiomers of these two compounds, ent-androsterone (ent-3) and ent-etiocholanolone (ent-4), have greater activity than steroids nat-3 and nat-4. Androsterone and ent-androsterone are aligned at a common binding site on GABAA receptors.

Because ent-3 and ent-4 are effective allosteric enhancers of GABA action at GABAA receptors, there is a need to research whether additional compounds having the absolute configuration of ent-3 and ent-4 could be effective allosteric modulators of GABAA receptor function.
In view of the foregoing, it is clear that there are a number of potentially advantageous uses for neurosteroids. As a result, there is a continuing need for the further synthesis and understanding of new neuroactive steroids, particularly those having utility as an anesthetic and/or in the treatment of a disorder relating to GABA function and activity.
The present disclosure has found previously unknown ent-steroids having this activity that are effective enhancers of GABAA receptor function.